Naltrexone Prodrugs for Transdermal Delivery

纳曲酮是一种阿片类拮抗剂，目前以口服片剂的形式用于帮助维持阿片类药物成瘾者处于无药状态。最近，纳曲酮被认为是治疗酒精依赖的一种辅助药物，并且据报道，在某些酗酒人群中，纳曲酮可以减少对酒精的渴望。对于阿片类药物成瘾者和酗酒者来说，透皮给药纳曲酮是可取的，以帮助减少与口服治疗相关的副作用并提高依从性。纳曲酮本身不具备必要的物理化学性质，不能使治疗剂量的药物通过人体皮肤屏障。我们计划继续设计和合成比纳曲酮更具皮肤渗透性的衍生物（前药），以制造治疗上成功的给药系统。我们假设纳曲酮的前药可以提高纳曲酮的透皮给药率，这些前药将成为研究透皮通量和并发代谢定量结构-渗透性关系（QSPRs）的良好研究工具。这些前药应该提高纳曲酮在皮肤上的递送率，因为它们更亲脂，更少结晶，因此比纳曲酮更容易溶解。该项目的具体目标包括：(1)合成一系列纳曲酮前药，旨在阐明纳曲酮前药的透皮通量和同步代谢的基本QSPRs；(2)表征纳曲酮前药的理化参数，包括分子量、分子体积、亲脂性、氢键势、熔点、熔合热和在选定溶剂中的溶解度；(3)测定纳曲酮前药在体外通过人体皮肤的渗透和同步代谢。(4)表征纳曲酮前药在豚鼠体内的药代动力学；(5)表征最有前途的纳曲酮前药在猪体内的药代动力学。我们的体外数据与体内模型的相关性将有助于建立可靠的QSPR数据库，并有助于确定最终用于人类的最有希望的前药。

Naltrexone, an opioid antagonist, is currently used in oral tablet form to help maintain opioid addicts in a drug-free state. Most recently, naltrexone has been indicated as an adjunct in the treatment of alcohol dependence, as well as reported to reduce alcohol craving in certain alcoholic populations. Transdermal delivery of naltrexone is desirable for opioid addicts and alcoholics in order to help reduce side effects associated with oral therapy and improve compliance. Naltrexone itself does not have the essential physicochemical properties that would allow a therapeutic dose of the drug to cross the human skin barrier. We plan to continue designing and synthesizing derivatives (prodrugs), which are more skin permeable than naltrexone, in order to make a therapeutically successful drug delivery system. We hypothesize that prodrugs of naltrexone will improve the transdermal delivery rate of naltrexone, and that these prodrugs will make excellent research tools for investigating quantitative structure- permeability relationships (QSPRs) for transdermal flux and concurrent metabolism. These prodrugs should improve naltrexone delivery rates across the skin, because they are more lipophilic, less crystalline, and therefore more soluble than naltrexone. The specific aims of this project include: (1) to synthesize a series of naltrexone prodrugs designed to elucidate fundamental QSPRs for transdermal flux and concurrent metabolism of the prodrugs, (2) to characterize the physicochemical parameters of the naltrexone prodrugs, including molecular weight, molecular volume, lipophilicity, hydrogen-bonding potentials, melting points, heats of fusion, and solubilities in select solvents, (3) to measure the naltrexone prodrugs' penetration and concurrent metabolism through human skin in vitro, (4) to characterize the pharmacokinetics of the naltrexone prodrugs in guinea pigs in vivo, and (5) to characterize the pharmacokinetics of the most promising naltrexone prodrugs in pigs in vivo. Correlation of our in vitro data with the in vivo models will aid in the creation of a reliable QSPR database, as well as help to identify the most promising prodrug for eventual human use.